Current and Emerging Therapeutics of Anxiety and Stress Disorders

66 CURRENT AND EMERGING THERAPEUTICS OF ANXIETY AND STRESS DISORDERS JACK M. GORMAN JUSTINE M. KENT JEREMY D. COPLAN During the 1960s and 1970s the concept of ‘‘pharmacologic began to accumulate from just a few studies that GAD dissection’’ became popular as a putative method for differ- might also respond to antidepressants. This evidence was entiating among different categories of psychiatric illness. largely ignored,and pharmaceutical companies were advised At the time,it was widely held that anxiety disorders,but to stay away from GAD,a condition supposedly so placebo- not depression,respond to benzodiazepines,whereas responsive that no drug would ever be shown effective in depression,but not anxiety disorders,responds to anti- large clinical trials. To the contrary,venlafaxine is now ap- depressants. Panic disorder was held to be the one exception, proved by the Food and Drug Administration (FDA) for responding only to antidepressants. Alprazolam,selective the treatment of GAD,and there is also evidence for the serotonin reuptake inhibitors (SSRIs),and buspirone had efficacy of paroxetine. not yet been tested. On the basis of these observations,it At this point,rather than ‘‘dissecting’’ among the anxiety was asserted that anxiety and depression are clearly distinct disorders or between anxiety disorders and depression,phar- categories of illness. macologic grounds might lead one to assume that these Thirty years later we find that the situation has changed conditions are variants of each other. This also would proba- dramatically. The first inconsistency with the notion of bly be an oversimplification. Anxiety and depression are pharmacologic dissection was the clear finding that panic different and we can make distinctions among the anxiety disorder does indeed respond to benzodiazepines. For a disorders. Nevertheless,the finding that antidepressants are while,alprazolam and then clonazepam were regarded by so ubiquitously effective across categories raises interesting some authorities and clinicians as first-line therapies for questions and challenges. We review here the evidence for panic disorder,replacing tricyclics and monoamine oxidase responsiveness of four anxiety disorders to medication. inhibitors. An even more potent challenge,however,has come from the evidence not only that anxiety disorders respond to anti- PANIC DISORDER depressants but also that antidepressants work better than benzodiazepines for most of them. As this chapter discusses, Panic disorder (PD) has a reported lifetime prevalence of antidepressants are now considered the appropriate pharma- between 1.5% and 3.5% (1,2), is highly comorbid with cologic intervention for panic disorder,social anxiety disor- major depression,and is associated in its own right with der,posttraumatic stress disorder (PTSD),and generalized significant impairment in psychosocial functioning inde- anxiety disorder (GAD). The latter case is particularly inter- pendent of depressive symptomatology. In the Epidemio- esting. Once considered the sole domain of benzodiaze- logic Catchment Area study,subjective reports of patients pines,GAD was then shown to be responsive to a drug in with PD indicate that approximately one-third experience an entirely new category,with no relationship whatsoever poor physical and emotional health,rates comparable with to the benzodiazepine receptor or ␥-aminobutyric acid major depression (2). (GABA)—buspirone. At about the same time evidence Historical Notes Jack M. Gorman, Justine M. Kent, and Jeremy D. Coplan: Columbia Recognized as a distinct disorder that could be distinguished University,New York State Psychiatric Institute,New York,New York. from the general diagnosis of ‘‘anxious neurosis,’’ in part 968 Neuropsychopharmacology: The Fifth Generation of Progress through the pharmacologic dissection work of Klein and greatest improvement in panic symptoms (10). Although Fink (3,4) in the 1960s, PD was first categorized as a discrete several other of the heterocyclic antidepressants have been diagnostic entity in the Diagnostic and Statistical Manual of used in the treatment of PD (amitryptyline,desipramine, Mental Disorders,third edition (DSM-III),in 1980. Despite nortriptyline,clomipramine),far less controlled data are some minor changes in diagnostic criteria in the third edi- available supporting their efficacy (11,12). Although effec- tion revised (DSM-III-R) and the fourth edition (DSM-IV), tive,side effects often limit the use of this class of medication primarily involving the number and frequency of attacks in the treatment of PD. This is particularly true in the case required,the major criteria remain essentially the same. The of clomipramine,which due to its anticholinergic and anti- key triad of symptoms are (a) the occurrence of spontaneous histaminergic effects can be difficult for patients to tolerate panic attacks; (b) the presence of anticipatory anxiety; and (13). The use of the heterocyclic antidepressants is often (c) the presence of phobic avoidance,resulting in some de- limited by the presence of comorbid medical conditions gree of functional impairment. The pharmacologic treat- such as cardiac disease and glaucoma. Lethality in overdose ment of PD has evolved dramatically since the heterocyclic is another concern given the reported high rates of suicide antidepressants were first established as possessing powerful in this population when depression is comorbid (14–16). antipanic properties in the early 1960s (4). Throughout the Although the SSRIs are often touted as offering a more 1970s and 1980s,the heterocyclic antidepressants contin- tolerable side-effect profile than the heterocyclics,the side- ued to be the mainstay of pharmacologic treatment of PD, effect burden of imipramine has recently been shown to be with the monoamine oxidase inhibitors (MAOIs) used pri- comparable to,although different in nature from,that of marily in patients who failed trials of heterocyclic antide- the SSRIs,with most side effects (with the exception of dry pressants. The high potency benzodiazepines were increas- mouth,sweating,and constipation) not persisting beyond ingly prescribed as both primary and adjunct treatments the first few weeks of treatment (17). throughout this same time period. With the introduction of the SSRIs in the United States in the late 1980s and early 1990s for the treatment of depression,this class of drug began being used in the treatment of PD with promis- Monoamine Oxidase Inhibitors ing results. In the late 1990s,several large-scale,controlled Like the heterocyclic antidepressants,the MAOIs,are trials established the SSRIs to be effective and safe treat- clearly established to be effective in the treatment of PD,yet ments for PD,thus supplanting the heterocyclic antidepres- have yielded to newer antidepressants with similar antipanic sants and benzodiazepines as first-line treatment. Although efficacies but less drug–drug and dietary interactions. the serotonin,norepinephrine,and GABA systems remain Among the MAOIs,phenelzine is the best studied in PD, the traditional targets for the majority of antipanic medica- and its efficacy in the acute treatment of PD is supported tions,widely different classes of drugs targeting an array of by several studies (18–20). Dietary restrictions,lethality in neurochemical systems are now being explored as potential overdose,and drug interaction concerns limit the wide- treatments for PD. spread use of the traditional MAOIs. Stemming from these concerns,the reversible inhibitors of MAOI (RIMAs) were Heterocyclic Antidepressants developed and have demonstrably fewer drug–drug and di- Numerous controlled trials have confirmed the efficacy of etary interactions. These include moclobemide and brofaro- the heterocyclic antidepressants,since the initial observa- mine,neither of which is currently marketed in the United tions of Klein (4),in both the acute and long-term treatment States,but are used extensively throughout Europe and of PD. In general,heterocyclics with greatest serotoninergic other parts of the world. The efficacy of moclobemide has reuptake inhibition effect,such as imipramine and clomi- been shown in the treatment of PD in placebo-controlled pramine,appear to be most effective in the treatment of studies (21),and moclobemide has been found to be compa- PD (5–7). By far the best studied of this class of antidepres- rable in efficacy to clomipramine (21) and fluoxetine (22). sants is imipramine,which due to its well-established effi- Moclobemide has also been shown to be as effective as fluox- cacy has been generally accepted as the gold standard of PD etine in maintenance treatment of PD (23). Brofaromine treatment (8). In the Cross-National Collaborative Panic was shown to be comparable to fluvoxamine (24) and clomi- Study,more than 1,000patients in 14 countries were ran- pramine (25) in small randomized,double-blind studies domized into a study comparing imipramine,alprazolam, lacking a placebo. In a placebo-controlled study of the effi- and placebo (9). At the study’s end,imipramine and alpra- cacy of brofaromine,30 patients with PD (DSM-III-R defi- zolam were found to have comparable efficacy,and both nition) were treated for 12 weeks. Although there was no were significantly superior to placebo on most outcome significant reduction in the number of panic attacks for measures. A positive dose–response relationship between those patients treated with brofaromine,patients demon- imipramine levels and clinical improvement has been re- strated clinical

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